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SYNTHESIS OF 1, 4
-DIHYROPYRIDINE
DERIVATIVES
INTRODUCTION
Dihydropyridine chemistry began in 1882 when Arthur Hantzsch (1) published the
synthesis which now bears his name. In the subsequent 50 years modifications
of the original synthesis were developed and some reactions of dihydropyridines
were studied. Dihydropyridines also play a role as intermediates in the reactions
of pyridines, e.g., in nucleophilic substitutions and reductions as well as
acylation in the presence of pyridine. Hantzsch assumed the product from the
reaction of ethyl aceto-acetate, acetaldehyde and ammonia now known to be a
2,3-dihydropyridine, but it was soon recognized to be the 1,4 isomer. However,
rigorous proof was presented only much later.
Number of 1,4-dihydropyridine derivatives have been synthesized by three
component condensation using aldehyde, ethyl aceto acetate and ammonium
acetate
(2)
also catalyst free and solvent free synthesis have been found using
.Bayer
(3)
and knovengel
(4)
Hantzsch reaction.
203
(5)
CHO
R
O
O
O
+ 2
R
+
R1 Liq.NH3
H2 O
50-60 C R
R
1
3
Me
Cozzy
and coworkers
have
(9)
Me
synthesized
series
of
4-phenyl-1,4-
204
(10)
METHOD OF PREPARATION
The synthesis of 1, 4 dihyropyridine derivatives was synthesized by a single
step reaction called as Hantzsch reaction. It is one step process.
REACTION SCHEME-1
Me
C2H5O2C
Me
CO2C2H5
CH2
+
C
CH3
H3C
O
CHO
NH4OH in ethanol
heated for 10hrs.
Me
Me
N
C2H5O
H3 C
OC2H5
CH3
2) Preparation of 3,5-diethyl-2,6-dimethyl-4-(2hyroxy-phenyl)-1,4-dihyropyridine-3,5dicarboxylate.
For
the
synthesis
of
3,5-diethyl-2,6-dimethyl-4-(2-hyroxyphenyl)-1,4
ethanol .when the solid product crystallized out; it was dried and recrystallized
with ethyl alcohol to remove for all impurities.
The 1,4- dihyropyridine named as [A2].
REACTION SCHEME-2
C 2H 5O 2 C
CO2C2H5
C
+
C
H3 C
CH2
+
OH
CH3
O
CHO
NH4OH in ethanol
heated for 8hrs.
OH
C2H5O
H3 C
OC2H5
CH3
3) Preparation of 3,5-diethyl-2,6-dimethyl-4-(pchloro-phenyl)-1,4-dihyropyridine-3,5dicarboxylate.
For
the
synthesis
of
3,5-diethyl-2,6-dimethyl-4-(p-chlorophenyl)
1,4
The reaction mixture was heated for 10hours on water bath .when the
precipitate were appear in the bottom of the flask reaction mixture were stand
for cool down. After that the mixtures was taken in another flask and carefully
add cold water. The precipitate was filtered off and
aqueous ethanol .when the solid product crystallized out; it was dried and
recrystallized with ethyl alcohol to remove for all impurities.
The 1,4- dihyropyridine named as [A3].
REACTION SCHEME-3:
Cl
C2H5O2C
CO2C2H5
C
C
CH2
H3C
CH3
O
CHO
NH4OH in ethanol
heated for 10hrs.
Cl
C2H5O
H3C
CH3
208
OC2H5
4) Preparation
of
3, 5-diethyl-2, 6-dimethyl- 4-
(p-methoxy phenyl)-1,4-dihyropyridine-3,5dicarboxylate.
A mixture of p-methoxy-benzaldehyde 12.1ml, ethyl aceto-acetate 25ml and
conc.ammonium hydroxide 3.8ml was taken in round bottom flask containing
25ml ethanol. Round bottom flask was fitted with a condenser the mixture was
heated for 5hours on water bath. The reaction was cooled the solid product was
filtered and washed with 60% aqueous ethanol. When the solid product was
completely dried out; recrystallized with ethyl alcohol. The 1,4 dihyropyridine
named as [A4]
REACTION SCHEME-4
209
OCH3
C2H5O2C
CO2C2H5
C
CH2
+
C
CH3
H3C
O
CHO
NH4OH in ethanol
heated for 5hrs.
OCH3
C2H5O
H3 C
CH3
210
OC2H5
References
211
212